Since 2008, outbreaks of atypical hand, foot, and mouth disease (HFMD) in children and adults have been reported worldwide. The majority of these outbreaks are caused by a new lineage of Coxsackie ...virus A6 (CV-A6) presenting a more severe clinical phenotype than the classical childhood HFMD caused by CV-A16. Between June 2014 and January 2016, 23 cases of atypical HFMD disease presented at a Dermatology Department at a regional University Hospital in Denmark. Patients were referred by general practitioners and dermatologists with a variety of clinical diagnoses, including eczema herpeticum, vasculitis, syphilis, dermatophytid, erythema multiforme and Stevens-Johnson syndrome. Three adults and 3 children required hospitalization due to extensive skin involvement and fever. All reported patients had laboratory-confirmed enterovirus infection. This study demonstrated an upsurge in atypical HFMD caused by CV-A6 in the Region of Southern Denmark and that atypical HFMD can be difficult to diagnose clinically as it may mimic other severe skin diseases.
: Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, ...sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR‐induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases‐dependent apoptotic pathways and involvement of poly(ADP‐ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm2), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin‐treated controls. Preincubation with melatonin also led to normalization of the decreased UVR‐induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway‐related initiator caspase 9 (casp‐9), but not of death receptor‐dependent casp‐8 between 24 and 48 hr after UVR exposure. Melatonin down‐regulated effector caspases (casp‐3/casp‐7) at 24–48 hr post‐UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV‐irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR‐induced damage of human keratinocytes.
We report helium isotope ratios (3He/4He) of lavas and tephra of the Rungwe Volcanic Province (RVP) in southern Tanzania. Values as high as 15RA (RA = air 3He/4He) far exceed typical upper mantle ...values, and are the first observation of plume‐like ratios south of the Turkana Depression which separates the topographic highs of the Ethiopia and Kenya domes. The African Superplume ‐ a tilted low‐velocity seismic anomaly extending to the core‐mantle boundary beneath southern Africa – is the likely source of these high 3He/4He ratios. High 3He/4He ratios at RVP together with similarly‐high values along the Main Ethiopian Rift and in Afar provide compelling evidence that the African Superplume is a feature that extends through the 670‐km seismic discontinuity and provides dynamic support – either as a single plume or via multiple upwellings – for the two main topographic features of the East Africa Rift System as well as heat and mass to drive continuing rift‐related magmatism.
Key Points
High 3He/4He ratios in Rungwe Volcanic Province
First observation of high 3He/4He for Kenya Dome
Widespread occurrence of deep‐seated African Superplume
Long-term trends of the incidence and outcome of cardiogenic shock (CS) patients are scarce. We analyze for the first time trends in the incidence and outcome of CS during a 20-year period in ...Switzerland.
The AMIS (Acute Myocardial Infarction in Switzerland) Plus Registry enrolls patients with acute myocardial infarction from 83 hospitals in Switzerland. We analyzed trends in the incidence, treatment, and in-hospital mortality of patients with CS enrolled between 1997 and 2017. The impact of revascularization strategy on outcome was assessed for the time period 2005 to 2017. Among 52 808 patients enrolled, 963 patients were excluded because of missing data and 51 842 (98%) patients remained for the purpose of the present analysis. Overall, 4090 patients (7.9%) with a mean age of 69.6±12.5 years experienced acute myocardial infarction complicated by CS. Overall, rates of CS declined from 8.7% to 7.3% between 1997 and 2017 ( P for trend, <0.001; 1997-2006 versus 2007-2017). We observed a decrease in CS developing during hospitalization from 7.8% to 3.5% in the period 1997 to 2006 compared with 2007 to 2017 ( P for trend, <0.001), which was partially offset by an increase in CS on admission between 2006 and 2017 (2.5% 1997-2006 to 4.6% 2007-2017; P for trend, <0.001). In-hospital mortality declined from 62.2% in 1997 to 36.3% in 2017 ( P<0.001 for temporal trend). Percutaneous coronary intervention was the strongest independent predictor for survival (odds ratio, 0.36; CI, 0.28-045; P<0.001). Among patients with acute myocardial infarction and multivessel disease, multivessel percutaneous coronary intervention was associated with an increased risk of in-hospital mortality (odds ratio, 1.88; 95% CI, 1.59-2.21) and was an independent predictor for the development of CS during hospitalization (odds ratio, 1.93; 95% CI, 1.62-2.30).
Rates of CS declined between 1997 and 2017 driven by a reduction of CS developing during hospitalization. In-hospital mortality from CS declined from 62.8% (1997) to <40% (2017). Multivessel percutaneous coronary intervention was associated with an increased risk of mortality and the development of CS during hospitalization.
Although spatial hearing is of great importance in everyday life, today’s routine audiological test batteries and static test setups assess sound localization, discrimination and tracking abilities ...rudimentarily and thus provide only a limited interpretation of treatment outcomes regarding spatial hearing performance. To address this limitation, we designed a dynamic sound field test setup and evaluated the sound localization, discrimination and tracking performance of 12 normal-hearing subjects. During testing, participants provided feedback either through a touchpad or through eye tracking. In addition, the influence of head movement on sound-tracking performance was investigated. Our results show that tracking and discrimination performance was significantly better in the frontal azimuth than in the rear azimuth. Particularly good performance was observed across the rear midline in localization, discrimination and tracking tests. As expected, free head movement improved sound-tracking abilities. Furthermore, feedback via gaze detection led to larger tracking errors than feedback via the touchpad. We found statistically significant correlations between the static and dynamic tests, which favor the snapshot theory for auditory motion perception.
The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the ...lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care.
A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months.
We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events.
Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.
Pyrrolysyl-tRNA synthetase (PylRS) is frequently used for site-specific incorporation of noncanonical amino acids (ncAAs) into proteins. Recently, the active site of
PylRS (
PylRS) has been ...rationally engineered to expand its substrate compatibility, enabling the incorporation of difficult ncAAs. However, mutations beyond the active site that enhance the enzymatic properties of
PylRS have not been reported. We utilized phage-assisted non-continuous evolution (PANCE) to evolve
PylRS to efficiently incorporate
-Boc-l-lysine (BocK). Directed evolution yielded several mutations outside of the active site that greatly improve the activity of the enzyme. We combined the most effective mutations to generate a new PylRS variant (PylRS
) that is highly active and selective towards several lysine and phenylalanine derivatives. The mutations in PylRS
can be used to enhance previously engineered PylRS constructs such as
PylRS
, and PylRS
is compatible in applications requiring dual ncAA incorporation and substantially improves the yield of these target proteins.
A 67-year-old patient was admitted to our hospital with lack of appetite and upper gastrointestinal bleeding. The immediately performed emergency gastroscopy showed a giant subepithelial tumour with ...ulceration located in the antrum. Emerging from the tumourous ulcer was a peg-shaped outgrowth reaching through the pylorus down to the duodenum causing gastric outlet obstruction. Based on this unusual presentation of a gastric giant lipoma we have reviewed the literature concerning differential diagnosis and treatment options.
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